The emerging interest in chronopharmacology demonstrates the fact that biological rhythms are an important aspect of clinical pharmacology and should be taken into account when evaluating drug delivery systems (Hrushesky, W., J.Cont. Rel. 19:363 (1992) and Lemmer, B., Adv. Drug Del. Rev. 6:19 (1991)). Studies indicate that the onset of certain diseases show strong circadian temporal dependency. This has led to the need for timed patterning of drug delivery as opposed to constant drug release. Currently, drug delivery modulation is being accomplished by external means, such as ultrasonic modulation, magnetic modulation and iontophoresis (Kost, J., Langer, R., Adv. Drug Del. Rev. 6:19 (1991)). Self-regulated delivery systems, only recently being discussed, are generally based on the enzymatic triggering of a functionalized polymer (Kost et al., above). A theoretical model of an oscillating chemical reaction of a membrane for periodic drug delivery has recently been published by Siegel and Pitt (Siegel, R. A. and Pitt, C. G., Proceed. Intern. Symp. Control Rel. Bioact. Mater., 20:49 (1993)). The present approach is for the passive periodic release of a drug or active ingredient utilizing oscillating chemical reactions, thus avoiding the need for external power sources and/or electronic controllers. In other words, once the oscillation reaction is begun, the oscillation reaction, and thereby the delivery of the active agent, is driven by the free energy of the system.
Chemical oscillating reactions have been known for about one hundred years. The most extensively investigated oscillator, the Belousov-Zhabotinskii (BZ) reaction, has been used as a model for studying a wide variety of temporal and spatial instabilities in chemical systems (Zhabotinskii, A. M. in Oscillations and Traveling Waves in Chemical Systems; Field, R. J., Burger, M., Eds.; Wiley-Interscience: New York, (1983)). BZ systems are generally accepted as the metal ion catalyzed oxidation and bromination of an organic substrate by acidic bromate. In the classic BZ reaction, the pH is fairly stable and not a driving force in the reaction.
The family of pH oscillators consist of those oscillating chemical reactions in which there is a large amplitude change in the pH and in which the pH change is an important driving force rather than merely a consequence or an indicator of the oscillation (Rabai, G. Orban, M. and Epstein, I. R. Acc. Chem. Res. 23:258 (1990) and Luo, Y. and Epstein, I. R. J. Am. Chem. Soc. 113:1518 (1991)). The pH of a solution can be oscillated over a range of pH values from 2 to 10 by the reduction and oxidation (redox) reactions of salts, such as permanganates, iodates, sulfates, chlorates, or bromates. The first pH oscillator, the hydrogen peroxide-sulfide reaction, was discovered only ten years ago. Approximately 14 pH oscillator systems are now known. These include the iodate-sulfite-thiourea system; the iodate-sulfite-thiosulfate system; the iodate-sulfite-ferrocyanide system; the iodate-hydroxylamine system; the periodate-hydroxylamine system; the periodate-thiosulfite system; the hydrogen peroxide-ferrocyanide system; the hydrogen peroxide-thiosulfate-copper(II) system; the hydrogen peroxide-bisulfite-thiosulfate system, the peroxodisulfate-thiosulfate-copper(II) system; the bromite-iodide system; the bromate-sulfite-ferrocyanide system; the bromate-sulfite-thiosulfate system; and the manganese(II)-periodate system. (See Luo and Epstein, above).
The CIMA reaction (chlorite/iodide/malonic acid) (J. Am. Chem. Soc. 1990, 112, 9104-9110) is a redox reaction in which the pH of the solution oscillates in response to, but does not drive, the oscillation reaction.
U.S. Pat. No. 4,756,710 (Bondi et al., 1988) describes a pH-mediated drug delivery system, in which a weakly acidic or basic unionized drug in a transdermal delivery system may be delivered continuously and at a relatively low rate. The pH control described there is to maintain a stable pH, not an oscillating one.
Other typical transdermal systems (without mentioning or utilizing oscillation reactions) which can be modified for use in the present invention include those described in: U.S. Pat. No. 4,781,924; U.S. Pat. No. 3,598,122; U.S. Pat. No. 4,597,961; U.S. Pat. No. 3,996,934; U.S. Pat. No. 4,911,707; U.S. Pat. No. 4,743,249; U.S. Pat. No. 4,917,676; U.S. Pat. No. 5,064,654; U.S. Pat. No. 5,073,539, each of which is incorporated herein by reference.
Oral osmotic systems, such as those embodied in products marketed under the Alza trademark OROS.RTM., typically have a semipermeable membrane which allows fluid into the device to dissolve material internal to the device, thereby creating an osmotic pressure and forcing the dissolved material through an orifice to the external environment. These devices are exemplified by, but not limited to, those in U.S. Pat. No. 4,326,525; U.S. Pat. No. 4,439,195; U.S. Pat. No. 4,455,143; and U.S. Pat. No. 3,916,899, each of which is incorporated herein by reference. These systems can be modified for use in the present invention.